This invention relates to topical compositions for application to human skin and to their use in improving the condition and appearance of skin.
Skin is subject to deterioration through dermatological disorders, environmental abuse (wind, air conditioning, and central heating) or through the normal aging process (chronoageing) which may be accelerated by exposure of skin to sun (photoageing). In recent years the demand for cosmetic compositions and cosmetic methods for improving the appearance and condition of skin has grown enormously.
Consumers are increasingly seeking xe2x80x9canti-ageingxe2x80x9d cosmetic products that treat or delay the visible signs of chronoageing and photoageing skin such as wrinkles, lines, sagging, hyperpigmentation and age spots.
Consumers also frequently seek other benefits from cosmetic products in addition to anti-ageing. The concept of xe2x80x9csensitive skinxe2x80x9d has also raised the consumer demand for cosmetic products that improve the appearance and condition of sensitive, dry and/or flaky skin and to soothe red, and/or irritated skin. Consumers also desire cosmetic products that have an oil/sebum control effect. Many people are concerned with the degree of pigmentation of their skin. For example, people with age spots or freckles may wish such pigmented spots to be less pronounced. Others may wish to reduce the skin darkening caused by exposure to sunlight or to lighten their natural skin colour. To meet this need many attempts have been made to develop products that reduce the pigment production in the melanocytes. However, the substances thus far identified tend to have undesirable side effects, e.g. skin irritation.
Consequently such substances are not suitable for cosmetic use or they can only be applied at a concentration at which their skin lightening effect is less than desired. Using a combination of different skin lightening substances may be considered to reduce adverse side effects but there is a substantial risk that by using such a combination the skin lightening is reduced as well due to competition effects. Therefore there is a need for improvement in the effectiveness of cosmetic skin lightening products particularly, such that they do not irritate the skin.
The use of fatty acids, including petroselinic acid, in cosmetic formulations for treating the hair is known. EP-A-116439) describes hair tonics which include fatty acids (such as petroselinic acid) for alleviating dandruff and itch and for stimulating hair growth.
EP-A 709084 describes the use of coriander seed oil, which is rich in petroselinic acid triglycerides, in a cosmetic composition for moisturising dry skin conditions. Retinol (vitamin A) is an endogenous compound that occurs naturally in the human body and is essential for normal epithelial cell differentiation. Natural and synthetic vitamin A derivatives (retinoids) have been used extensively in the treatment of a variety of skin disorders and have been used as skin repair or renewal agents. Retinoic acid, for example, has been employed to treat a variety of skin conditions, e.g., acne, wrinkles, psoriasis, age spots and discoloration. See e.g., Vahlquist, A. et al., J. Invest. Dermatol., Vol. 94, Holland D. B. and Cunliffe, W. J. (1990), pp. 496-498; Ellis, C. N. et al., xe2x80x9cPharmacology of Retinols in Skinxe2x80x9d, Vasel, Karger, Vol. 3, (1989), pp. 249-252; Lowe, N. J. et al., xe2x80x9cPharmacology of Retinols in Skinxe2x80x9d, Vol. 3, (1989), pp. 240-248, PCT Patent Application No. WO 93/19743.
There continues to be a need, however, for alternative effective cosmetic compositions for topical application to skin for treating/delaying the visible signs of aging and photodamaged skin such as wrinkles, lines, sagging, hyperpigmentation and age spots.
We have now found that effective treatment and prevention of normal, (but cosmetically undesirable), skin conditions, due to chronoageing or photoageing, such as wrinkles, lines, sagging, hyperpigmentation and age spots, may be obtained through the application of cosmetic compositions to the skin which comprise a specific fatty acidxe2x80x94petroselinic acid and/or derivatives thereof, in combination with a retinoid and/or an inhibitor of the enzyme acyl CoA retinol transferase (ARAT) or the enzyme lecithin retinol acyl transferase (LRAT) (hereinafter referred to as LRAT/ARAT inhibitors). We have also found that the use of such cosmetic compositions advantageously provides further skin care benefits in addition to anti-ageing such as soothing sensitive and/or irritated skin, controlling oil/sebum secretion and for lightening the skin.
The art discussed above does not disclose the specific synergistic combination of petroselinic acid with retinoids/LRAT/ARAT inhibitors nor the use of such a specific combination for treating wrinkles sensitive skin, dry skin, controlling oil/sebum secretion, or lightening skin.
According to a first aspect of the present invention there is provided a topical composition comprising:
(a) petroselinic acid and/or derivatives thereof;
(b) a retinoid and/or an LRAT/ARAT inhibitor; and
(c) a dermatologically acceptable vehicle.
According to a second aspect of the present invention there is provided a cosmetic method of providing at least one skin care benefit selected from: treating/preventing wrinkling, sagging, dry, aged and/or photodamaged skin; boosting collagen deposition in skin, boosting decorin production in skin, enhancing tissue repair; soothing irritated, red and/or sensitive skin; improving skin texture, smoothness and/or firmness; lightening skin; controlling oil/sebum secretion, the method comprising applying to the skin a topical composition as described above.
The present invention also encompasses the use of the inventive compositions for providing at least one skin care benefit selected from treating/preventing wrinkling, sagging, aged and/or photodamaged skin; boosting collagen deposition in skin, boosting decorin production in skin, enhancing tissue repair; soothing irritated, red and/or sensitive skin; improving skin texture, smoothness and/or firmness; lightening skin; controlling oil/sebum secretion.
According to a still further aspect of the present invention there is provided the use of petroselinic acid and derivatives thereof in combination with a retinoid and/or a LRAT/ARAT inhibitor in a cosmetic topical composition for providing at least one cosmetic skin care benefit selected from treating/preventing wrinkling, sagging, aged and/or photodamaged skin; boosting collagen deposition in skin, boosting decorin production in skin, enhancing tissue repair; soothing irritated, red and/or sensitive skin; improving skin texture, smoothness and/or firmness; lightening skin; and controlling oil/sebum secretion.
The inventive compositions, methods and uses thus provide anti-aging benefits which result in the promotion of smooth and supple skin with improved elasticity and a reduced or delayed appearance of wrinkles and aged skin, with improved skin colour. A general improvement in the appearance, texture and condition, in particular with respect to the radiance, clarity, and general youthful appearance of skin is achieved. The inventive compositions, methods and uses are also beneficial for soothing and calming sensitive and/or irritated skin, for lightening skin and for controlling oil/sebum secretion. Thus the present invention advantageously provides a wide range of skin care benefits.
The term xe2x80x9ctreatingxe2x80x9d as used herein includes within its scope reducing, delaying and/or preventing the above mentioned normal skin conditions such as wrinkled, aged, and/or photodamaged, and/or irritated skin and generally enhancing the quality of skin and improving its appearance and texture by preventing or reducing irritation, wrinkling and increasing flexibility, firmness, smoothness, suppleness and elasticity of the skin, all for cosmetic purposes. The compositions, methods and uses according to the invention may be useful for treating skin which is already in a wrinkled, aged, photodamaged, irritated condition or for treating youthful skin to prevent or reduce those aforementioned undesirable changes due to the normal ageing/photoageing process.
Petroselinic Acid
Petroselinic acid (hereinafter referred to as PA) is a monounsaturated long chain (C18) fatty acid, having the formula CH3(CH2)10CHxe2x95x90CH(CH2)4COOH.
The invention also includes derivatives of the free acid which thus comprise petroselinic acid moieties. Preferable derivatives include those derived from substitution of the carboxyl group of the acid, such as esters (eg triglyceride esters, monoglyceride esters, diglyceride esters, phosphoesters), amides (eg ceramide derivatives), salts (eg alkali metal and alkali earth metal salts, ammonium salts); and/or those derived from substitution of the C18 carbon chain, such as alpha hydroxy and/or beta hydroxy derivatives.
In the case of triglyceride ester derivatives, all positional isomers of PA substituents on the glycerol backbone are included. The triglycerides must contain at least one PA moiety. For example, of the three esterifiable positions on the glycerol backbone, the 1 and 2 positions may be esterified with PA and by another lipid at position 3 or as an alternative, the glycerol backbone could be esterified by PA at the 1 and 3 positions with another lipid at position 2.
Oils that are rich in petroselinic acid triglyceride are thus also suitable for use in the present invention. Such oils are commercially available and include parsley seed oil, carrot seed oil, fennel fruit oil, parsnip seed oil, coriander seed oil, chervil seed oil, caraway plant oil, and celery seed oil.
Wherever the term xe2x80x9cpetroselinic acidxe2x80x9d or xe2x80x9cPAxe2x80x9d is used in this specification it is to be understood that the derivatives thereof comprising PA moieties are also included. xe2x80x9cPA moietiesxe2x80x9d refers to PA fatty acyl portion(s) of a PA derivative.
The PA to be employed in accordance with the present invention is present in the topical composition in an effective amount. Normally the total amount of the active is present in an amount between 0.0001% and 50% by weight of the composition. More preferably the amount is from 0.01% to 10% and most preferably from 0.1% to 5% in order to maximize benefits at a minimum cost.
Retinoid
The term xe2x80x9cretinoidxe2x80x9d inter alia includes retinoic acid, retinoyl ester, retinol, retinyl ester.
The term xe2x80x9cretinolxe2x80x9d includes the following isomers of retinol: all-trans-retinol, 13-cis-retinol, 11-cis-retinol, 9-cis-retinol, 3,4-didehydro-retinol. Preferred isomers are all-trans-retinol, 13-cis-retinol, 3,4-didehydro-retinol, 9-cis-retinol. Most preferred is all-trans-retinol, due to its wide commercial availability.
Retinyl ester is an ester of retinol. The term xe2x80x9cretinolxe2x80x9d has been defined above. Retinyl esters suitable for use in the present invention are C1-C30 esters of retinol, preferably C2-C20 esters, and most preferably C2-C3, and C16 esters because they are more commonly available. The preferred esters for use in the present invention are selected from, retinyl palmitate, retinyl acetate, retinyl propionate and retinyl linoleate, because these are the most commercially available and therefore the cheapest. Retinyl ester is also preferred due to its efficacy.
Retinoyl ester is an ester of retinoic acid. Retinoyl esters suitable for use in the present invention include C1-C30 esters of retinoic acid, preferably C2-C20 esters and most preferably C2-C3 and C16 esters. The preferred esters for use in the present invention are selected from retinoyl linoleate, retinoyl palmitate, retinoyl oleate, retinoyl ascorbate, and retinoyl linolenate.
LRAT/ARAT Inhibitor
Retinol is an endogenous compound that occurs naturally in the human body and is essential for normal epithelial cell differentiation. Esters of retinol hydrolyze in-vivo to produce retinol. It is believed that retinyl esters and retinol are metabolically converted in the skin into retinoic acid according to the following mechanism 
However, most of the endogenously applied retinol is rapidly converted into inactive fatty esters for storage in epidermal cells (keratinocytes).
Esterification of retinol into inactive retinyl esters is achieved in cells by transfer of a fatty acyl group from an acyl CoA, catalyzed by the enzyme acyl CoA retinol transferase (ARAT), or by the transfer of an acyl group from phosphatidyl choline, catalyzed by the enzyme lecithin retinol acyl transferase (LRAT). These esterification reactions are very efficient in keratinocytesxe2x80x94the majority (95%) of cellular retinoids are in the form of retinyl fatty esters.
The term xe2x80x9cLRAT/ARAT inhibitorxe2x80x9d in the present application thus means an agent which inhibits these esterification reactions and thus potentiates the action of retinol by increasing the amount of retinol available for conversion to retinoic acid.
The LRAT/ARAT inhibitors within the scope of the present invention are identifiable as those compounds which at 100 xcexcM concentration inhibit at least 20% of LRAT or ARAT catalyzed retinol esterification as measured by the in vitro Microsomal Assay described below in Example 1. In a preferred embodiment of the invention, the LRAT/ARAT inhibitor is a compound that at 100 xcexcM concentration inhibits at least 40% and most preferably at least 50% of LRAT or ARAT catalysed retinol esterification. The in vitro Microsomal Assay employed for determining whether or not a compound is such a LRAT/ARAT inhibitor is as described in Example 1 below.
Thus if a compound passes this in vitro Microsomal assay, that is, it inhibits sufficiently an LRAT or ARAT catalysed retinol esterification as measured by the in vitro Microsomal Assay, it is included in the present invention even if it is not specifically mentioned herein.
Examples of such LRAT/ARAT inhibitors which satisfy the assay described in Example 1 include fatty acid amides, hydroxy fatty acid amides, ceramides, melinamide, imidazolidinones, and cyclic aliphatic unsaturated hydrocarbons, terpenes, and fatty hydroxyethyl imidazoline surfactants.
Cyclic Aliphatic Unsaturated Compounds
Suitable cyclic aliphatic unsaturated compounds are selected according to the in-vitro Microsomal Assay Test described above.
A preferred cyclic aliphatic unsaturated compound is selected from cyclic aliphatic unsaturated aldehydes, ketones, alcohols and esters such as alpha damascone, beta damascone, delta damascone, isodamascone, damascenone, alpha ionone, beta ionone, allyl alpha ionone, isobutyl ionone, alpha methyl ionone, gamma methyl ionone, brahmanol, sandanol, alpha terpineol, lyral, ethyl saffranate, and mixtures thereof. Preferably, in order to maximize performance at a minimum cost, a cyclic aliphatic unsaturated compound is selected from the group consisting of damascones and ionones.
Most preferably, the cyclic aliphatic unsaturated compound is a xcex1-Damascone and/or xcex1-Ionone.
Diterpenes
Suitable diterpenes are selected according to the in-vitro Microsomal Assay Test described above. A preferred diterpene compound is geranyl geraniol, which is a potent inhibitor of retinol esterification.
Fatty Hydroxethyl Imidazoline Surfactants
Fatty hydroxyethyl imidazoline surfactants included in the present invention pass the in-vitro Microsomal Assay test described above. Preferred fatty hydroxyethyl imidazolines have the following general structure: 
wherein R is an aliphatic saturated or unsaturated, straight or branched hydro-carbon chain containing from 8 to 20 carbon atoms.
Preferably, R in the fatty hydroxyethyl imidazoline contains from 8 to 18 carbon atoms, more preferably from 11 to 18 carbon atoms. Most preferably, the fatty hydroxyethyl imidazoline is oleyl hydroxyethyl imidazoline, due to its commercial availability and efficacy.
Fatty Acid Amide
Preferably, the fatty acid amide contains at least 6 carbon atoms. Suitable fatty acids include saturated and unsaturated, straight or branched fatty acids. Suitable fatty acids preferably contain from 8 to 24 carbon atoms, preferably from 12 to 20 carbon atoms, and most preferably from 12 to 18 carbon atoms, because longer chain fatty acid amides are more beneficial for conditioning of the skin. In the most preferred embodiment of the invention, amides of essential fatty acids are employed because essential fatty acids provide nutrition for the skin. Examples of essential fatty acids include but are not limited to linoleic, linolenic, arachidonic, gamma-linolenic, homo-gamma-linolenic, and mixtures thereof. Linoleic acid is most preferred because it is also a precursor to ceramide.
The preferred amides included in the present invention are mono- and di-alkanol amides, particularly of essential fatty acids. Alkanol amides are more commonly available than alkyl amides.
The most preferred fatty acid amides are selected from mono- and diethanolamides and phosphatidylethanolamides of linoleic acid, palmitic acid, and coconut oil; diethyl cocamide, linoleamidyl dimethylamine, dimethyl linoleamide, diethyl linoleamide, dimethyl palmitide, myristoyl sarcosine.
Hydroxy Fatty Acid Amides
The structure of an amide of a hydroxy fatty acid is as follows: 
wherein
R1, R2 and R4 each is independently selected from hydrogen and aliphatic saturated or unsaturated, straight or branched hydrocarbon chains which may be hydroxylated, containing from 1 to 20 carbon atoms;
R3 is xe2x80x94(CH2)n where n is an integer from 0 to 18;
Preferably, R1, R2, R4 each independently contains from 2 to 20 carbon atoms, more preferably from 2 to 15 carbon atoms, most preferably from 3 to 13 carbon atoms.
Preferably the hydroxy acid amide is an amide of xcex1- or xcex2-hydroxy acid, i.e., n is 0 or 1.
The most preferred hydroxy fatty acid amides to be included in the inventive compositions are: lactamide-monoethanolamide, C13-xcex2-hydroxy acid amide (2-hydroxy-C13-amide), N-hydroxyethyl-2-hydroxy-C16 amide, 12-hydroxy-N-(2-hydroxyethyl) octadecanamide, and monoethanolamide of castor oil.
Polycyclic Triterpene Carboxylic Acid (PTCA)
A further example of a suitable LRAT/ARAT inhibitor is a PCTA which passes the in vitro Microsomal Assay.
Preferably the PTCA is a pentacyclic triterpene monocarboxylic acid.
Most preferably, PTCA is selected from the group consisting of ursolic acid, oleanolic acid, glycerrhetinic and glycyrrhizic acid.
PTCA are commercially available from Aldrich and Sigma. Plant extracts containing PTCA are suitable for use in the present invention e.g. Rosmarinus officinalis (rosemary), Diospyros spp. (persimmon), Forsythia suspensa (forsythia), Lavandula angustifolia (lavender), Prunella vulgaris (selfheal), Paeonia lactifolia, Glycyrrhiza glabra (licorice).
It should be understood that depending on the pH of the composition, PTCA may be present in the composition as a salt, e.g. alkali or alkaline earth salt.
Ceramides
The ceramides may for example be naturally occurring ceramides, phyto ceramides, short chain ceramides, pseudoceramides or neoceramides. The general structure of these molecules is described in U.S. Pat. No. 5,476,661 (Pillai et al.) whose contents are hereby incorporated by reference.
The most preferred ceramide derivative is acetyl sphingosine due to its efficacy.
The retinoid and/or LRAT/ARAT inhibitor can be included in the inventive compositions in an amount ranging from 0.0001% to 50% by weight of the composition, preferably it is used in an amount of from 0.01% to 10%, most preferably from 0.1% to 5%.
Dermatologically Acceptable Vehicle
The composition used according to the invention also comprises a dermatologically/cosmetically acceptable vehicle to act as a dilutant, dispersant or carrier for the actives.
The vehicle may comprise materials commonly employed in skin care products such as water, liquid or solid emollients, silicone oils, emulsifiers, solvents, humectants, thickeners, powders, propellants and the like.
The vehicle will usually form from 5% to 99.9%, preferably from 25% to 80% by weight of the composition, and can, in the absence of other cosmetic adjuncts, form the balance of the composition.
Optional Skin Benefit Materials and Cosmetic Adjuncts
Besides the actives, other specific skin-benefit actives such as sunscreens, other skin lightening agents, skin tanning agents may also be included. The vehicle may also further include adjuncts such as perfumes, opacifiers, preservatives, colourants and buffers.
Product Preparation, Form, Use and Packaging
To prepare the topical composition used in the method of the present invention, the usual manner for preparing skin care products may be employed. The active components are generally incorporated in a dermatologically/cosmetically acceptable carrier in conventional manner. The active components can suitably first be dissolved or dispersed in a portion of the water or another solvent or liquid to be incorporated in the composition. The preferred compositions are oil-in-water or water-in-oil or water-in-oil-in-water emulsions.
The composition may be in the form of conventional skin-care products such as a cream, gel or lotion, capsules or the like. The composition can also be in the form of a so-called xe2x80x9cwash-offxe2x80x9d product e.g. a bath or shower gel, possibly containing a delivery system for the actives to promote adherence to the skin during rinsing. Most preferably the product is a xe2x80x9cleave-onxe2x80x9d product, i.e. a product to be applied to the skin without a deliberate rinsing step soon after its application to the skin.
The composition may packaged in any suitable manner such as in a jar, a bottle, tube, roll-ball, or the like, in the conventional manner. It is also envisaged that the inventive compositions could be packaged as a kit of two separate compositions one containing the petroselinic acid and the second containing the retinoid/LRAT/ARAT inhibitor compound, to be applied to the skin simultaneously or consecutively.
The composition according to the present invention may also be formulated in a form suitable for oral ingestion such as a capsule, tablet or the like.
The method of the present invention may be carried out one or more times daily to the skin which requires treatment. The improvement in skin appearance will usually become visible after 3 to 6 months, depending on skin condition, the concentration of the active components used in the inventive method, the amount of composition used and the frequency with which it is applied. In general, a small quantity of the topical composition, for example from 0.1 to 5 ml is applied to the skin from a suitable container or applicator and spread over and/or rubbed into the skin using the hands or fingers or a suitable device. A rinsing step may optionally follow depending on whether the composition is formulated as a xe2x80x9cleave-onxe2x80x9d or a xe2x80x9crinse-offxe2x80x9d product.